The vast majority of cancers of the lung, breast and colon are adenocarcinomas, which arise from pre-existing adenomatous polyps that develop in the normal colonic mucosa. This adenoma-carcinoma sequence is a well-characterized clinical and histopathologic series of events with which discrete molecular genetic alterations have been associated. Lung tumor development and metastasis are complex processes that include transformation, proliferation, resistance to apoptosis, neovascularization, and metastatic spread. A number of gene products have been identified that play critical roles in these processes. It has been suggested that the development of epithelial-derived tumors, the most common class of cancers, involves mutations of tumor suppressors and proto-oncogenes or epigenetic alterations of signaling pathways affecting cell proliferation and/or survival, which in turn may be caused by inflammation induced by infections and reactive oxygen species (ROS) (Ernst, P. Aliment Pharmacol Ther., 1999, 13(1):13-18).
A group of four peptide hormones, originating from the 126-amino acid atrial natriuretic factor (ANF) prohormone, have become known for their vasodilator activity. These four peptide hormones, consisting of amino acids 1-30, 31-67, 79-98, and 99-126 of this prohormone, have been named long acting natriuretic peptide (LANP), vessel dilator (VD), kaliuretic peptide (KP), and atrial natriuretic peptide (ANP), respectively, for their most prominent effects (Angus R. M. et al., Clin Exp Allergy 1994, 24:784-788). The ANP sequence, particularly the C-terminal portion, is highly conserved among species (Seidman et al., Science, 1984, 226:1206-1209). ANP has been proposed to be useful for treatment of various cardiovascular, respiratory, and renal diseases (Vesely, D. L. Cardiovascular, 2001, 51:647-658), but also causes inflammation. The family of natriuretic hormone peptides has been shown to have broad physiologic effects, including vasodilation and inhibition of aldosterone secretion and cardiovascular homeostasis.
As indicated above, ANF, the 126 amino acid prohormone, gives rise to four peptides: LANP (amino acids 1-30), VD (amino acids 31-67), KP (amino acids 79-98) and ANP (amino acids 99-126, also referred to herein as NP99-126) (Angus R. M. et al, Clin Exp Allergy, 1994, 24:784-788). The ANP sequence particularly the C-terminal portion is highly conserved among species (Seidman et al., Science, 1984, 226: 1206-1209). The natriuretic peptide receptors (NPRs), NPR-A and NPR-B, are expressed in many different tissues of various organs systems, and are coupled to guanylyl cyclase. ANP and BNP are thought to signal primarily through NPR-A by increasing cGMP and activating cGMP-dependent protein kinase (PKG). NPR-A is the primary receptor for ANP while NPR-B seems to bind CNP most effectively. PKG activation in turn activates ion transporters and transcription factors, which together affect cell growth and proliferation, apoptosis and inflammation. NPR-C is a clearance receptor for ANP removal, but also appears to signal phospholipase C activation and a decrease in adenylyl cyclase activity through a cGMP-independent pathway (Abbey and Potter, Endocrinology, 2003, 144: 240-246; Silberbach and Roberts, Cell Signal, 2001, 13:221-231). The signaling mechanisms underlying ANP's growth regulatory effects are poorly understood, although a number of reports suggest that ANP acts through mitogen-activated protein kinases (Silberbach and Roberts, Cell Signal, 2001, 13:221-231).
Most cells of the mucosal immune system have ANP receptors (NPRs) and there is evidence that natriuretic peptides regulate the immune response and inflammation (Kurihara et al., Biochem Biophys Res Commun 1987, 149:1132-1140). ANP stimulates migration of human neutrophils (Izumi et al., J Clin Invest 2001, 108:203-213), and inhibit nitric oxide and TNF-α production by murine macrophages (Kiemer and Vollmar, J Biol Chem 1998, 273:13444-13451; Kiemer et al., J Immunol 2000, 165:175-81). It has been suggested that the ANP system may be a critical component of the immune response through its actions on both immune and non-immune cells. In patients with lung tumors, the immune response plays a large part in the progression of the disease and, consequently, the NPR system may potentially be involved. The alveolar macrophages in lung cancer patients secrete more pro-inflammatory cytokines, such as IL-6 and IL-1β, after LPS stimulation than in persons with non-malignant disease (Matanic et al., Scand J Immunol 2003, 57:173-178). Increased IL-6 in lung cancer patients enhances the acute phase response, and is correlated with h poor nutritional status and lowered survival (Martin et al., Cytokine 1999, 11; 267-273). The cells of the immune system, such as natural killer (NK) cells, Vα24 NKT, which are necessary for cancer surveillance may also be reduced in lung tumor patients (Motohashi et al., Int J Cancer 2002, 102:159-165). The most common clinical paraneoplastic syndrome in patients with small-cell lung cancer (SCLC) is hyponatremia, which is believed to be caused by tumor secretion of vasopressin. Tumor biopsies from patients with SCLC and hyponatremia expressed the gene for ANP (Shimizu et al., Cancer 1991, 68: 2284-2288; Bliss et al., J Natl Can Inst, 1990, 82: 305-310). Thus, the reduced sodium levels seen in SCLC patients may be attributed to the secretion of ANP (Bliss et al., J Natl Can Inst, 1990, 82: 305-310). Human SCLC cell lines express functional ANP receptors (Ohsaki et al., Cancer Res 1993, 53: 3165-3171). A majority of SCLC cell lines produce ANP and some produce BNP as well (Ohsaki et al., Oncology 1999, 56:155-159). In contrast, in NSCLC cell lines, which are derived mostly from adenocarcinomas that comprise about two-thirds of all lung cancers, little is known about their growth regulation in response to ANP cascade.
The present inventor has found that the N-terminal natriuretic peptides, such as pNP73-1102, are capable of inhibiting NFκB activation (Mohapatra, international application WO 2004/022003, published Mar. 18, 2004, which is incorporated herein by reference in its entirety), and that the ANP cascade plays a critical role in cell proliferation and inflammation. NFκB, a transcription factor and a key player in inflammatory processes, has been implicated in the development of cancer in liver and mammary tissues (Greten F. R. et al. Cell, 2004, 118: 285-296; Pikarsky F. et al. Nature, 2004, 431: 461-466). Activation of the NF-κB pathway enhances tumor development and may act primarily in the late stages of tumorigenesis. Inhibition of NF-κB signaling uniformly suppressed tumor development; however, depending upon the model studied, this salutary effect was attributed to an increase in tumor cell apoptosis, reduced expression of tumor cell growth factors supplied by surrounding stromal cells, or abrogation of a tumor cell dedifferentiation program that is critical for tumor invasion/metastasis.